EP0442655B1 - Benzisoxazole derivatives - Google Patents

Benzisoxazole derivatives Download PDF

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Publication number
EP0442655B1
EP0442655B1 EP91300958A EP91300958A EP0442655B1 EP 0442655 B1 EP0442655 B1 EP 0442655B1 EP 91300958 A EP91300958 A EP 91300958A EP 91300958 A EP91300958 A EP 91300958A EP 0442655 B1 EP0442655 B1 EP 0442655B1
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Prior art keywords
compound
formula
alkyl
mixture
solution
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EP91300958A
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German (de)
English (en)
French (fr)
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EP0442655A2 (en
EP0442655A3 (en
Inventor
Ewan James Turner Chrystal
John Edward Duncan Barton
David Cartwright
C. J. Mathews
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Syngenta Ltd
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Zeneca Ltd
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Priority claimed from GB909003557A external-priority patent/GB9003557D0/en
Priority claimed from GB909023985A external-priority patent/GB9023985D0/en
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Publication of EP0442655A3 publication Critical patent/EP0442655A3/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • A01N43/80—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/20—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings condensed with carbocyclic rings or ring systems

Definitions

  • the present invention relates to novel substituted benzisoxazole derivatives, processes for their preparation, their use as herbicides and herbicidal compositions containing them.
  • a compound of formula (I) in which Ar is an aryl or heterocyclic ring system which may be optionally substituted by up to 5 members selected from halogen, alkyl containing up to 3 carbon atoms, haloalkyl, haloalkoxy, nitro, cyano, alkoxy containing up to 3 carbon atoms, or S(O) p R d where p is 0, 1 or 2 and R d is alkyl; R1 and R2 are independently selected from H; halogen; NR a R b ; alkyl, alkenyl or alkynyl, each of which may be optionally substituted by one or more groups selected from halo, nitro, nitrile, aryl, CO2R11, NHCOR11 or NHCH2CO2R11 (wherein R11 is hydrogen, C1 ⁇ 6 alkyl or an agriculturally acceptable cation), C1 ⁇ 6 alkoxy, oxo, S(O)
  • alkyl includes straight or branched chains containing up to 10 carbon atoms preferably from 1 to 6 carbon atoms.
  • alkenyl and “alkynyl” refer to unsaturated straight or branched chains having from 2 to 10 and preferably from 2 to 6 carbon atoms.
  • cycloalkyl includes rings containing from 3 to 9 carbon atoms, preferably from 3 to 6 carbon atoms.
  • alkoxy includes straight or branched chains containing up to 10 carbon atoms preferably from 1 to 6 carbon atoms.
  • lower used in relation to alkyl, alkenyl or alkynyl groups means that the group contains up to 3 carbon atoms.
  • haloalkyl and haloalkoxy refer to alkyl and alkoxy groups respectively substituted by at least one halogen atom such as fluorine, chlorine or bromine. A particular haloalkyl group is trifluoromethyl.
  • aryl includes phenyl and naphthyl.
  • heterocyclic includes rings of up to 10 atoms, preferably up to 6 atoms up to 3 of which are selected from oxygen, nitrogen or sulphur.
  • halogen includes fluorine, chlorine, bromine and iodine.
  • a suitable aryl ring system is phenyl.
  • Suitable heterocyclic ring systems for R6, R7 and Ar are rings of up to 10 atoms, up to 3 of which are selected from oxygen, nitrogen or sulphur, preferably aromatic ring systems such as pyridine and pyrazole.
  • Suitable optional substitutents for the aryl or heterocyclic ring systems Ar and for the aryl groups R a , R b , R c , R4, R5, R6, R7, R8 and R9 are up to 5 preferably up to 3 members selected from halogen (fluoro, chloro, bromo or iodo), lower alkyl, haloalkyl (for example CF3), haloalkoxy (for example OCF3), nitro, cyano, lower alkoxy (for example methoxy) or S(O) p R d where p is 0, 1 or 2 and R d is alkyl (for example thiomethyl, sulphinylmethyl and sulphonylmethyl).
  • Preferred positions of substitution when the aryl ring Ar is a phenyl ring are the 2, 4 and 6 positions, particularly 2,4,6-tri- substituted rings with a trifluoromethyl group at the 4-position.
  • Examples of optional substituents for alkyl, alkenyl, alkynyl groups R a , R b , R c , R1, R2, R4, R5, R6, R7, R8 and R9, include one or more groups selected from halo such as fluoro, chloro or bromo; nitro; nitrile; aryl such as phenyl; CO2R11, NHCOR11 or NHCH2CO2R11 wherein R11 is hydrogen, C1 ⁇ 6 alkyl or an agriculturally acceptable cation; C1 ⁇ 6 alkoxy; oxo; S(O) p R d where p is 0, 1 or 2 and R d is alkyl (for example thiomethyl, sulphinylmethyl and sulphonylmethyl); amino; mono- or di- C1 ⁇ 6 alkylamino; CONR12R13 wherein R12 and R13 are independently selected from hydrogen, C1 ⁇ 6 alkyl, C2 ⁇ 6 alkenyl or C2
  • Examples of agriculturally acceptable cations M+ and R11 include sodium, potassium or calcium ions, sulphonium or sulphoxonium ions or for example of formula S+(O) q R6R7R8 where q is 0 or 1 and R6, R7 and R8 are as hereinbefore defined, ammonium or tertiary ammonium ions of formula N+R6R7R8R9 where R6, R7, R8 and R9 are as hereinbefore defined.
  • Suitable substituents for the alkyl, alkenyl and alkynyl groups in these cations are hydroxy and phenyl.
  • any of R6, R7, R8 and R9 in the cations are optionally substituted alkyl, they contain from 1 to 4 carbon atoms.
  • R6, R7, R8 and R9 in these cations are hydrogen, ethyl, isopropyl, benzyl and 2-hydroxyethyl.
  • Examples of agriculturally acceptable anions for Y ⁇ are halides, tetrafluoroborate, mesylate and tosylate ions.
  • Suitable halo groups R1, and R2 include fluorine, chlorine and bromine.
  • Suitable heterocyclic rings formed from two of R a , R b , R6, R7, R8 and R9 and the atom to which they are attached are pyrrolidine, piperidine and morpholine.
  • R1 is H.
  • R2 is H or is C1 ⁇ 3 alkyl, in particular methyl or ethyl .
  • R4 is preferably alkyl or substituted alkyl for example alkoxyalkyl or oxo substituted alkyl.
  • a preferred example of R4 is C1 ⁇ 6 alkyl, especially methyl.
  • Ar is preferably a group: where R18 is N, CH or CR20 and R19 and R20 are independently selected from halogen, such as chlorine or fluorine.
  • R18 is CR20 and most preferably one of C19 and C20 is chlorine and the other is fluorine.
  • Another group Ar is optionally substituted pyrazole, for example optionally substituted by Cl, CF3 and CH3.
  • W is preferably oxygen.
  • the formula (I) given above is intended to include tautomeric forms of the structure drawn, as well as physically distinguishable modifications of the compounds which may arise, for example, from different ways in which the molecules are arranged in a crystal lattice, or from the inability of parts of the molecule to rotate freely in relation to other parts, or from geometrical isomerism, or from intra-molelcular or inter-molecular hydrogen bonding, or otherwise.
  • the compounds of the invention can exist in enantiomeric forms.
  • the invention includes both individual enantiomers and mixtures of the two in all proportions.
  • Compounds of formula (I) may be prepared by reacting a compound of formula (II) : wherein W, R1, R2 and R3 are as defined in relation to formula (I) with a compound of formula (III) : Ar-Z (III) wherein Ar is as defined in relation to formula (I) and Z is a leaving group, optionally in the presence of a base.
  • Suitable leaving groups Z include halogen, such as fluorine, bromine and chlorine, and sulphonates such as methanesulphonate and p -toluenesulphonate.
  • Suitable bases for use in the reaction include bases such as sodium hydride, and alkali metal carbonates and hydroxides.
  • the reaction is preferably carried out in an organic solvent such as dimethylformamide, dimethylsulphoxide, a lower alkanol, or a lower ketone.
  • organic solvent such as dimethylformamide, dimethylsulphoxide, a lower alkanol, or a lower ketone.
  • Moderate temperatures for example of from 10°C to 200°C are suitably employed.
  • Conveniently the reaction is carried out at 50°C to 150°C.
  • reaction product may consist of a mixture of regioisomers. These isomers may be inseparable and mixture composition is analysed by 1H NMR and 19F NMR, when appropriate.
  • Dihydroxycoumarins are known compounds and compounds of formula (III) are known compounds or may be prepared from known compounds by conventional methods.
  • Suitable bases for use in the reaction include bases such as alkali metal hydroxides, carbonates and alkoxides.
  • the reaction is preferbly carried out in an organic solvent such as dimethylformamide, dimethyl sulphoxide or a lower alkanol.
  • organic solvent such as dimethylformamide, dimethyl sulphoxide or a lower alkanol.
  • Moderate temperatures for example from 10°C to 120°C are suitably employed.
  • Conveniently the reaction is carried out at 20°C to 110°C.
  • Compounds of formula (IV) may be prepared by the reaction of compound of formula (V) : with a suitable derivative of carbonic acid, for example ethyl chloroformate or diethyl carbonate, in the presence of a base.
  • a suitable derivative of carbonic acid for example ethyl chloroformate or diethyl carbonate
  • Suitable bases for use in the reaction include bases such as alkali metals, alkali metal hydrides or alkoxides.
  • the reaction may be carried out in either the presence of absence of solvent. If a solvent is employed, suitable solvents are for example toluene, dimethylformamide, dimethyl sulphoxide or terahydrofaran. Moderate temperatures, for example from 50°C to 150°C are suitably employed. Conveniently the reaction is carried out at 70°C to 120°C.
  • Compounds of formula (V) may be prepared from compounds of formula (VI) : by a Lewis acid catalysed Fries rearrangement.
  • Aluminium trichloride is a suitable catalyst.
  • the reaction may be carried out in the absence of solvent. Higher temperatures, for example 100°C to 200°C are suitably employed.
  • Compounds of formula (VIII) and (IX) may be prepared by the reaction of a compound of formula (X) : Ar-WH (X) wherein Ar and W are as defined in relation to formula (I) and a compound of formula (XI) : wherein U is COCH3 or NO2 and Z is a leaving group as defined for formula (III), optionally in the presence of a base.
  • Suitable bases for the reaction include bases such as sodium hydride, alkali metal carbonates and hydroxides, and organic nitrogen bases, for example triethylamine, 4-dimethylamino pyridine or 4-pyrolidinopyridine.
  • the reaction is preferably carried out in an organic solvent such as dimethylformamide, dimethyl sulphoxide a lower alkanol, a chlorinated solvent or a lower ketone.
  • organic solvent such as dimethylformamide, dimethyl sulphoxide a lower alkanol, a chlorinated solvent or a lower ketone.
  • Moderate temperatures for example 10°C to 200°C are suitably employed.
  • the reaction is carried out at 50°C to 180°C.
  • compounds of formula (V) may be prepared from amines of formula (XII): where Ar and W are defined in relation to formula (I), by diazotisation followed by decomposition of the diazonium salt.
  • Suitable reagents for diazotisation are sodium nitrite in aqueous acid, for example hydrochloric acid at a temperature of -10 to 10°C.
  • the diazonium compound may be precipitated as the tetrafluoroborate salt.
  • the tetrafluoroborate salt of the diazonium compound may be decomposed by an alkali carbonate, eg potassium carbonate under acidic conditions, eg neat TFA, at elevated temperatures, for example 30-100°C, followed by an aqueous work up.
  • the tetrafluoroborate salt of the diazonium compound may be decomposed under aqueous conditions by copper salts, eg a mixture of cupric nitrate and cuprous oxide, at elevated temperatures, for example 30-100°C.
  • the compounds of formula (XII) may be prepared by reduction of nitro compounds of formula (XIII): wherein Ar and W are as defined in relation to formula (I).
  • the nitro compound is reduced in a solution in an organic solvent, for example ethanol, by hydrogen or a source of hydrogen, for example hydrazine, using a catalyst, for example Raney nickel at moderate temperatures, for example 20 to 120°C.
  • a solution of the nitro compound (XIII) in an organic solvent, for example ethanol or acetone may be reduced by an aqueous solution of titanium trichloride initially at low temperatures, for example -25 to 10°C.
  • Compounds of formula (XIII) may be prepared from the reaction of compounds of formula (X) with compounds of formula (XIV): where Z is a leaving group as defined in formula (III), optionally in the presence of base.
  • Suitable bases for the reaction include bases such as sodium hydride, alkali metal carbonates and hydroxides, and organic nitrogen bases, for example triethylamine, 4-dimethylaminopyridine or 4-pyrrolopyridine.
  • the reaction is preferably carried out in an organic solvent such as DMF, dimethyl sulphoxide, a lower alkanol, a chlorinated solvent or a lower ketone.
  • organic solvent such as DMF, dimethyl sulphoxide, a lower alkanol, a chlorinated solvent or a lower ketone.
  • Moderate temperatures for example 10 to 200°C are suitably employed.
  • the reaction is carried out at 50 to 70°C.
  • An alternative method for preparing compounds of formula (I) is by reacting a compound of formula (XV) : wherein Ar and W are as defined in relation to formula (I) and Z' is a leaving group such as halogen with a compound of formula (XVI) : where R1, R2 and R3 are as defined in relation to formula (I) in the presence of a base.
  • Suitable bases for use in the reaction include bases such as sodium hydride, alkali metal alkoxides and alkali metal bistrimethylsiyl amides.
  • the reaction is preferably carried out in an organic solvent such as dimethylformamide, dimethylsulphoxide, or tetrahydrofuran.
  • organic solvent such as dimethylformamide, dimethylsulphoxide, or tetrahydrofuran.
  • Moderate temperatures for example of from -78°C to 100°C are suitably employed.
  • the compounds of formula (I) are active as herbicides and therefore, in a further aspect the invention provides a process for severely damaging or killing unwanted plants which process comprises applying to the plants, or to the growth medium of the plants, an effective amount of a compound of formula (I) as hereinbefore defined.
  • the compounds of formula (I) are active against a broad range of weed species including monocotyledenous and dicotyledonous species. They may show some selectivity towards certain species; they may be used as selective herbicides in cotton, soya, maize, sugar beet and wheat crops.
  • the compounds of formula (I) may be applied directly to the plant (post-emergence application) or to the soil before the emergence of the plant (pre-emergence application). They are particularly useful when applied post-emergence.
  • the compounds of formula (I) may be used on their own to inhibit the growth of, severely damage, or kill plants but are preferbly used in the form of a composition comprising a compound of the invention in admixture with a carrier comprising a solid or liquid diluent.
  • the invention provides plant growth inhibiting, plant damaging, or plant killing compositions comprising a compound of formula (I) as hereinbefore defined and an inert carrier or diluent.
  • compositions containing compounds of formula (I) include both dilute compositions, which are ready for immediate use, and concentrated compositions, which require to be diluted before use, usually with water.
  • the compositions Preferbly the compositions contain from 0.01% to 90% by weight of the active ingredient.
  • Dilute compositions ready for use preferbly contain from 0.01% to 2% of active ingredient, while concentrated compositions may contain from 20% to 90% of active ingredient, although from 20% to 70% is usually preferred.
  • the solid compositions may be in the form of granules, or dusting powders wherein the active ingredient is mixed with a finely divided solid diluent, e.g. kaolin, bentonite, kieselguhr, dolomite, calcium carbonate, talc, powdered magnesia, Fuller's earth and gypsum. They may also be in the form of dispersible powders or grains, comprising a wetting agent to facilitate the dispersion of the powder or grains in liquid. Solid compositions in the form of a powder may be applied as foliar dusts.
  • a finely divided solid diluent e.g. kaolin, bentonite, kieselguhr, dolomite, calcium carbonate, talc, powdered magnesia, Fuller's earth and gypsum.
  • a finely divided solid diluent e.g. kaolin, bentonite, kieselguhr, dolomite
  • Liquid compositions may comprise a solution or dispersion of an active ingredient in water optionally containing a surface-active agent, or may comprise a solution or dispersion of an active ingredient in a water-immiscible organic solvent which is dispersed as droplets in water.
  • Surface-active agents may be of the cationic, anionic, or non-ionic type or mixtures thereof.
  • the cationic agents are, for example, quaternary ammonium compounds (e.g. cetyltrimethylammonium bromide).
  • Suitable anionic agents are soaps; salts of aliphatic mono esters of sulphuric acid, for example sodium lauryl sulphate; and salts of sulphonated aromatic compounds, for example sodium dodecylbenzenesulphonate, sodium, calcium, and ammonium lignosulphonate, butylnaphthalene sulphonate, and a mixture of the sodium salts of diisopropyl and triisopropylnaphthalenesulphonic aid.
  • Suitable non-ionic agents are the condensation products of ethylene oxide with fatty alcohols such as oleyl alcohol and cetyl alcohol, or with alkylphenols such as octyl- or nonyl-phenol (e.g. Agral 90) or octyl-cresol.
  • Other non-ionic agents are the partial esters derived from long chain fatty cids and hexitol anhydrides, for example sorbitan monolaurate; the condensation products of the partial ester with ethylene oxide; and the lecithins; silicone surface active agents (water soluble surface active agents having a skeleton which comprises a siloxane chain e.g. Silwet L77).
  • a suitable mixture in mineral oil is Atplus 411F.
  • aqueous solutions or dispersions may be prepared by dissolving the active ingredient in water or an organic solvent optionally containing wetting or dispersing agent(s) and then, when organic solvents are used, adding the mixture so obtained to water optionally containing wetting or dispersing agent(s).
  • organic solvents include, for example, ethylene di-chloride, isopropyl alcohol, propylene glycol, diacetone alcohol, toluene, kerosene, methylnaphthalene, the xylenes and trichloroethylene.
  • compositions for use in the form of aqueous solutions or dispersions are generally supplied in the form of a conentrate containing a high proportion of the active ingredient, and the concentrate is then diluted with water before use.
  • the concentrates are usually required to withstand storage for prolonged periods and after such storage, to be capable of dilution with water to form aqueous preparations which remain homogenous for a sufficient time to enable them to be applied by conventional spray equipment.
  • Concentrates conveniently contain 20-90%, preferably 20-70%, by weight of the active ingredient(s).
  • Dilute preparations ready for use may contain varying amounts of the active ingredients(s) depending upon the intended purpose; amounts of 0.01% to 10.0% and preferably 0.1% to 2%, by weight of active ingredient(s) are normally used.
  • a preferred form of concentrated composition comprises the active ingredient which has been finely divided and which has been dispersed in water in the presence of a surface-active agent and a suspending agent.
  • Suitable suspending agents are hydrophilic colloids and include, for example, polyvinylpyrrolidone and sodium carboxymethylcellulose, and the vegetable gums, for example gum acacia and gum tragacanth.
  • Preferred suspending agents are those which impart thixotropic properties to, and increase the viscosity of the concentrate. Examples of preferred suspending agents include hydrated colloidal mineral silicates, such as montmorillonite, beidellite, nontronite, hectorite, saponite, and suacorite. Bentonite is especially preferred.
  • Other suspending agents include cellulose derivatives and polyvinyl alcohol.
  • the rate of application of the compounds of the invention of the will depend on a number of factors including, for example, the compound chosen for use, the identity of the plants whose growth is to be inhibited, the formulations selected for use and whether the compound is to be applied for foliage or root uptake. As a general guide, however, an application rate of from 0.001 to 20 kilograms per hectare is suitable while from 0.005 to 1 kilograms per hectare may be preferred.
  • compositions of the invention may comprise, in addition to one or more compounds of the invention, one or more compounds not of the invention but which possess biological activity for example herbicides, fungicides, insecticides (optionally with an insecticide synergist) or a plant growth regulator.
  • the invention provides a herbicidal composition comprising a mixture of at least one herbicidal compound of formula (I) as hereinbefore defined with at least one other herbicide.
  • the other herbicide may be any herbicide not having the formula (I). It will generally be a herbicide having complementary action in the particular application.
  • Example herbicides, fungicides, insecticides (optionally with an insecticidal synergist) or a plant growth regulator for example herbicides, fungicides, insecticides (optionally with an insecticidal synergist) or a plant growth regulator.
  • Examples of useful complementary herbicides include:
  • the aqueous solution was acidified with concentrated hydrochloric acid and then extracted with diethyl ether.
  • the ether extract was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to give a yellow-orange solid, 5-hydroxy-1,2-benzoxazol-3-ylacetic acid (O.29g, 54%), m.p. 170°C (decomposition).
  • a catalytic quantity of dimethylaminopyridine and dicyclohexylcarbodiimide (0.26g) were added to a solution of compound 1 (prepared as in Example 1) (0.45g) in dry dichloromethane (10cm3) which was cooled with an ice bath. Propargyl alcohol (0.07g) was added, the ice bath removed and the reaction mixture stirred and allowed to warm to room temperature. After 3 hours, a precipitate was removed by filtration through hiflow and washed with dichloromethane. The washings and filtrate were combined and concentrated under reduced pressure.
  • the components of the mixture were quantified by 19F NMR.
  • the material obtained (6.28g) was purified by column chromatography (silica 4x35cm/hexane-diethyl ether, 7:3) to give compound 26 as the major component of a mixture which was a pale yellow oil (3.49g, 67%).
  • the mixture consisted of compound 26 (79%), a regioisomer of compound 26 (18%) and compound 8 (3%) by 19F NMR.
  • the oil was purified by preparative thin layer chromatogrphy (silica/hexane-diethylether, 8:2) to give compound 28 as the major component of a mixture which was a pale yellow oil (0.31g, 64%).
  • the mixture consisted of compound 28 (82%), a regioisomer of compound 28 (15%) and compound 8 (3%) by 19F NMR.
  • the faster eluting material was compound 35 (0.21g,8%), a solid, m.p. 121-124°C.
  • Compound 45 was prepared in an analogous manner using appropriate reagents.
  • the slower eluting material was compound 34 (0.71g, 51%) a soft solid.
  • the material obtained (5.43g) was purified by column chromatography (silica 3x30cm/hexane-diethyl ether, 7:3) to give compound 48 as the major component of a mixture, a pale yellow solid (3.53g, 65%), m.p. 72-74°C.
  • the mixture consisted of compound 48 (77%) and 2 isomers by 19F NMR.
  • a O.5M solution of potassium bis(trimehylsilyl)amide in touluene (9.7cm3) was added to a solution of compound 48 (1.72g), prepared as described in Example 22, in dry THF (10cm3) cooled by a dry ice/ethanediol bath. After cooling and stirring for 1.75 hours, methyl iodide (0.69g in 3.78cm3 dry THF) was added, and the reaction mixture then allowed to warm to room temperature overnight. The mixture was poured into water and extracted with diethyl ether. The ether extract was washed with brine, dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure.
  • the concentrate (1.94g) was purified by preparative thin layer chromatography (silica/hexane-diethylether, 7:3) to give compound 49 as a component of mixture, a pale yellow oil (0.98g, 55%), containing compound 49 (81%) and two other isomers of compound 49 (15% and 4%) by 19F NMR.
  • Compound 52 was prepared in an analogous manner using appropriate reagents and starting material.
  • Compound 53 was prepared in an analogous manner from appropriate reagents and starting material.
  • Compound 64 and 66 were prepared in an analogous procedure using appropriate reagents and starting materials.
  • Potassium hydroxide (4 pellets) was added to a solution of compound 5 (0.55g), prepared as described in Example 6, in methanol (15cm3) and the mixture heated at reflux for 1 hour. After cooling the mixture was poured into water, washed with diethyl ether, acidified with concentrated HCl and extracted with diethyl ether. The ether extract was washed with brine, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The white solid (0.40g) was used in step B without further purification.
  • step A The solid (0.38g) from step A was dissolved in methanol (25ml). After the addition of concentrated sulphuric acid (2cm3) the mixture was heated at reflux for 6 hours. After cooling, the mixture was poured into water and extracted with diethyl ether. The ether extract was washed with brine, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The material obtained (0.28g) was purified by preparative thin layer chromatography (silica/hexane-diethylether, 7:3) to give compound 65 (0.07g, 17%) a white solid, m.p. 85-86°C.
  • step A The oil from step A was dissolved in dry dichloromethane (10cm3) and the solution cooled with an ice/salt bath. Excess dimethylamine was added by pipette, the ice bath removed and the reaction mixture allowed to warm to room temperature. After stirring at room temperature for 11 ⁇ 2 hours, the reaction mixture was poured into water and extracted with dichloromethane. The dichloromethane extract was washed with dilute hydrochloric acid, aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The material obtained (0.3g) was purified by preparative thin layer chromatography (silica/ether) to give compound 67 (0.15g, 45%) as initially a colourless oil, which slowly solidified to a soft solid on standing.
  • the acid washings were made basic and extracted with diethyl ether.
  • the second diethyl ether extract was washed with brine, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure.
  • the material from the two ether extractions (0.17g and 0.04g respectively) were combined and purified by preparative thin layer chromatography (silica/ether with a few drops of acetic acid) to give a compound 68 (0.08g, 28%) as a white solid, m.p. 181-182°C.
  • Compound 70 was prepared in an analogous manner from compound 1 using appropriate reagents and starting material.
  • 1,2,3-Trichloro-5-trifluoromethylbenzene (3.29g) and potassium carbonate (3.3g) were added to a solution of methyl 5-hydroxy-1,2-benzoxazol-3-ylacetate (2.5g), prepared as described in step A of Example 2, in dry DMSO (15cm3).
  • the reaction mixture was heated at 100°C for 3.75 hours. After cooling, the mixture was poured into water and extracted with diethyl ether. The ether extract was washed with brine, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure.
  • the material obtained (3.78g) was purified by preparative thin layer chromatography to give compound 72 as the major component (92%) of a mixture of isomers (1.43g, 28%) a white solid, m.p. 99-100°C.
  • Compound 75 was prepared in an analogous manner using appropriate reagents and starting material.
  • Compound No. 87 was prepared in an analagous procedure from Compound No. 86 using appropriate reagents and starting materials.
  • Lithium alumuniumhydride (0.12g) was suspended in dry diethyl ether (15mls) under a nitrogen atmosphere and cooled using an ice bath. A solution of Compound No. 2 (0.6g) prepared as described in Example 2, in dry diethyl ether (5ml) was added slowly. The ice bath was removed and the solution allowed to warm to room temperature overnight.
  • Example 40 Step A The gum from Example 40 Step A, was dissolved in dry dichloromethane (10cm3) and the solution cooled with an ice bath. Benzyl alcohol (0.09g) followed by triethylamine (0.08g) were added giving white fumes, the ice bath was removed and the mixture allowed to warm to room temperature overnight.
  • Compound No. 85 was prepared in an analogous manner from Compound No. 1 using aprropriate reactants.
  • Potassium carbonate 13.82g was suspended in a DMSO solution (100cm3) containing 2,4-dichlorophenol (8.15g) and warmed to approximately 100°C to give a grey solution. 18-Crown-6 (0.13g) and 4-fluoroacetophenone (6.04cm3) were added. The mixture was warmed to 150°C and stirred overnight.
  • the oil (0.3g) was purified by preparative thin layer chromatography (silica/hexane-Et2O, 10:1) 4-(2,4-dichlorophenoxy)phenylacetate as a yellow oil (0.21g, 79%).
  • the reaction flask was plunged in to an oil bath at 90°C.
  • the two solids formed a brown oil which was stirred, as the temperature was raised to 140°C and held for 30 minutes.
  • the heat was removed and the mixture allowed to cool to room temperature to give a solid browm lump.
  • the aqueous extract was acidified with dilute hydrochloric acid and a cream precipitate formed which was filtered, washed with water and air dried to give 6-(2,4-dichlorophenoxy)-4-hydroxycourmarin (4.44g 89%) as a cream solid m.p 213-221°C dec.
  • Compound No. 100 was prepared from compound No. 2 in an analogous manner using appropriate reagents.
  • a 0.5m solution of potassium bis(trimethylisilyl)amide in toluene (4.36cm3) was added dropwside to a solution of compound 2, produced as in Example 2, (0.8g) in dry THF (20cm3) and cooled with a dry ice/ethanediol/isopropanol bath. The mixture was cooled and stirred for one hour at approximately -40°C. Allyl bromide (0.19cm3) in dry THF (2cm3) was added and the mixture stirred at -40°C for one hour before being allowed to warm to room temperature. A yellow solid precipitated out of solution as the temperature rose.
  • the oil obtained was purified three times by preparative thin layer chorotography (silica/hexane-ethyl acetate 2:1, 4:1 and 7:1) to give compound 112 (0.53g 60%) as an oil and compound 113 (0.04g, 4%) as an oil.
  • the nitroacetophenone prepared in Step B (11.0g, 30.5mmol) was dissolved in acetone (180cm3) and cooled to 10°C. Titanium trichloride (30% aqueous solution, 130cm3) was added dropwise over 30 minutes, and once the addition was complete the reaction mixture was allowed to warm to room temperature. The mixture was poured into water and extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried (MgSO4) filtered and the solvent removed in vacuo to afford a brown solid. Trituration with 60-80 petroleum ether gave 2-amino-5-(4-chloro-1-methyl-5-trifluoromethyl-1H-pyrazol-3-yloxy)acetophenone (10.0g) m.p. 90-92°.
  • the amine prepared in step C (10.0g, 30.3mmol) was suspended in water (120cm3) and acidified with concentrated hydrochloric acid. The mixture was cooled in an ice-salt bath and a solution of sodium nitrite (2.3g, 33.3mmol) in water (25cm3) was added dropwise and after the addition was complete the mixture was stirred at 0°C for 20 minutes. A solution of fluoroboric acid (20cm3) was added with vigorous stirring. When the addition was complete the reaction mixture was allowed to warm to room temperature. The precipitate was collected and dried.
  • the solid prepared above was added to a solution of cupic nitrate trihydrate (167.9g, 695mmol) in water (350ml) followed by cuprous oxide (4.29g, 29.2mmol). The mixture was stirred at room temperature for 15 minutes, then stirred at 45°C for 6 hours. The mixture was cooled to room temperature and extracted with dichloromethane. The organic extracts were combined, dried (MgSO4), filtered and evaporated in vacuo.
  • aqueous phase was extracted with ethyl acetate and then acidified with dilute aqueous hydrochloric acid and extracted once more with ethyl acetate.
  • the organic extract was dried (MgSO4) and the solvent removed in vacuo to afford 6-(4-chloro-1-methyl-5-trifluoromethyl-1H-pyrazol-3-yloxy)-4-hydroxycoumarin (1.95g) as a waxy solid.
  • reaction mixture was poured into ice/water and extracted with ethyl acetate.
  • organic extracts were combined, dried (MgSO4) evaporated in vacuo and the residue purified by flash column chromatography on silica gel, eluting with ethyl acetate/hexane (1:3) to give compound 121 (0.57g) as a pale yellow gum.
  • a suspension of compound 68, prepared as described in Example 29, (0.35g) was suspended in toluene (10cm3) with Lawesson's Reagent (0.2g) and the mixture heated at reflux for 1.75 hours. During the heating the suspension disolved to give a solution. On cooling to room temperature a solid formed and the reaction mixture was poured into water and extracted with diethylether. The extract was washed with water and brine, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The residue of the ether extract was further purified by preparative thin layer chromatography (silica/chloroform) to give compound 123 as a yellow solid (0.05g, 14%) m.p. 170-172°C.
  • Tween 20 is a Trade Mark for a surface-active agent comprising a condensate of 20 molar proportions of ethylene oxide with sorbitan laurate.
  • Span 80 is a Trade Mark for a surface-active agent comprising sorbitan mono-laurate.
  • the volume was made up to 5cm3 with water, glass beads were added and this mixture was then shaken to effect dissolution or suspension of the chemical, after which the beads were removed. In all cases, the mixture was then diluted with water to the required spray volume. If sprayed independently, volumes of 25cm3 and 30cm3 were required for pre-emergence and post-emergence tests respectively; if sprayed together, 45cm3 was required.
  • the sprayed aqueous emulsion contained 4% of the initial solvent/surfactant mix and the test chemical at an appropriate concentration.
  • the spray compositions so prepared were sprayed onto young pot plants (post-emergence test) at a rate equivalent to 1000 litres per hectare. Damage to plants was assessed 13 days after spraying by comparison with untreated plants, on a scale of 0 to 9 where 0 is 0% damage, 1 is 1-5% damage, 2 is 6-15% damage, 3 is 16-25% damage, 4 is 26-35% damage, 5 is 36-59% damage, 6 is 60-69% damage, 7 is 70-79% damage, 8 is 80-89% damage and 9 is 90-100% damage.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Wood Science & Technology (AREA)
  • Environmental Sciences (AREA)
  • Plant Pathology (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Dentistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Agronomy & Crop Science (AREA)
  • Zoology (AREA)
  • Pest Control & Pesticides (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Separation Using Semi-Permeable Membranes (AREA)
  • Detergent Compositions (AREA)
  • Air Bags (AREA)
  • Pyridine Compounds (AREA)
  • Pyrane Compounds (AREA)
EP91300958A 1990-02-16 1991-02-06 Benzisoxazole derivatives Expired - Lifetime EP0442655B1 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB9003557 1990-02-16
GB909003557A GB9003557D0 (en) 1990-02-16 1990-02-16 Heterocyclic compounds
GB9023985 1990-11-05
GB909023985A GB9023985D0 (en) 1990-11-05 1990-11-05 Heterocyclic compounds

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EP0442655A2 EP0442655A2 (en) 1991-08-21
EP0442655A3 EP0442655A3 (en) 1992-07-08
EP0442655B1 true EP0442655B1 (en) 1996-01-17

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US5484763A (en) * 1995-02-10 1996-01-16 American Cyanamid Company Substituted benzisoxazole and benzisothiazole herbicidal agents
US6339099B1 (en) * 1997-06-20 2002-01-15 Dupont Pharmaceuticals Company Guanidine mimics as factor Xa inhibitors
IL125947A0 (en) * 1997-09-17 1999-04-11 American Cyanamid Co 3-(1,2-benzisothiazol- and isoxazol-5-yl)-2,4(1h,3h)-pyrimidinedione or thione and 3-(1,2-benzisothiazol- and isoxazol-5-yl)-4(3)-pyrimidinone or thione herbicidal agents
US6156700A (en) * 1997-09-17 2000-12-05 American Cyanmid Company 3-(1,2-Benzisothiazol- and isoxazol-5-yl)-2,4(1H,3H)-pyrimidinedione or thione and 3-(1,2-benzisothiazol- and isoxazol-5-yl)-4(3H)-pyrimidinone or thione herbicidal agents
US7135575B2 (en) * 2003-03-03 2006-11-14 Array Biopharma, Inc. P38 inhibitors and methods of use thereof
CN110862367A (zh) * 2019-11-18 2020-03-06 上海兆维科技发展有限公司 一种香豆素芳基醚类化合物及其制备方法与应用

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GB8426367D0 (en) * 1984-10-18 1984-11-21 Shell Int Research Heteroaromatic ether herbicides
US4571225A (en) * 1984-10-31 1986-02-18 Modern Machine Works Inc. Sheave assembly
US4738709A (en) * 1985-01-10 1988-04-19 Ppg Industries, Inc. Herbicidally active substituted benzisoxazoles
GB2192879A (en) * 1986-07-23 1988-01-27 Shell Int Research Phenoxybenzisoxazole herbicides
GB2192878A (en) * 1986-07-23 1988-01-27 Shell Int Research Phenoxybenzisoxazole herbicides
US4898874A (en) * 1986-09-15 1990-02-06 A. H. Robins Company, Inc. Acetic acid derivatives of 3-aryl-2,1-benzisoxazole and esters and amides thereof
US4888041A (en) * 1987-05-18 1989-12-19 The Dow Chemical Company Grain selective herbicides
US4911754A (en) * 1987-07-16 1990-03-27 American Cyanamid Company Herbicidally active aryloxy saturated 5-membered benzo fused hetero-cyclic compounds

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DE69116392D1 (de) 1996-02-29
HUT56240A (en) 1991-08-28
FI910748A0 (fi) 1991-02-15
US5176737A (en) 1993-01-05
YU27291A (sh) 1994-04-05
TW215435B (pt) 1993-11-01
NO910617D0 (no) 1991-02-15
KR910015551A (ko) 1991-09-30
MA22064A1 (fr) 1991-10-01
BR9100615A (pt) 1991-10-29
PT96770A (pt) 1991-10-31
ZW991A1 (en) 1991-10-09
IL97102A0 (en) 1992-03-29
CS38891A2 (en) 1991-09-15
IE910279A1 (en) 1991-08-28
EP0442655A2 (en) 1991-08-21
CN1054064A (zh) 1991-08-28
NO910617L (no) 1991-08-19
FI910748A (fi) 1991-08-17
EP0442655A3 (en) 1992-07-08
CA2035184A1 (en) 1991-08-17
JPH04234858A (ja) 1992-08-24
NZ236951A (en) 1992-11-25
DE69116392T2 (de) 1996-06-13
GB9102905D0 (en) 1991-03-27
AU633680B1 (en) 1993-02-04
ATE133166T1 (de) 1996-02-15
PL289083A1 (en) 1992-07-13

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